GRP 146 Receptor

Abstract

We disclose GPR146 G-protein coupled receptor (GPCR) polypeptides comprising the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO: 5, and homologues, variants and derivatives thereof. Nucleic acids capable of encoding GPR146 polypeptide are also disclosed, in particular, those comprising the nucleic acid sequences shown in SEQ ID No. 1A, SEQ ID No.1 B, SEQ ID No.2 or SEQ ID NO: 4. The GPR146 receptor is useful in the diagnosis and therapy of dyslipidaemias.

1 . A method of identifying an agent suitable for therapy of a dyslipidaemia comprising the step of determining whether a candidate agent affects the activity of GPR146. 
     
     
         2 . The method according to  claim 1 , wherein the agent is an antagonist that inhibits the activity of GPR146. 
     
     
         3 . The method according to  claim 1 , wherein the agent is an agonist that enhances the activity of GPR146. 
     
     
         4 . The method according to  claim 1 , wherein the GPR146 comprises or encodes a polypeptide identified herein as SEQ ID NO:4 or SEQ ID NO:6, or a sequence with at least 70% sequence identity thereto. 
     
     
         5 . The method according to  claim 1 , wherein the GPR146 consists of or encodes a polypeptide identified herein as SEQ ID NO:4, SEQ ID NO:6, or a sequence with at least 70% identity thereto. 
     
     
         6 . The method according to  claim 1 , wherein the dyslipidaemia is Atheromatous disease, Atherosclerosis, Coronary Heart Disease, Dyslipidemia/Dyslipoproteinemia including hypercholesterolemia, Gall Bladder Disease, Impaired glucose tolerance, Insulin resistance, Metabolic Syndrome X, Obesity, Restenosis, Septic shock, Stroke, Type 2 diabetes, Angina pectoris, Transient ischemic attacks (TIAs) or Peripheral artery disease (PAD). 
     
     
         7 . The method according to  claim 1 , wherein GPR146 polypeptide is contacted with the candidate agent to determine whether the candidate affects the activity of the GPR146. 
     
     
         8 . The method according to  claim 1 , wherein the candidate agent is contacted with a cell expressing a GPR146 polypeptide. 
     
     
         9 . The method according to  claim 1 , comprising the steps of administering the candidate agent to a non-human animal expressing a GPR146 polypeptide and determining whether the animal exhibits altered lipid metabolism. 
     
     
         10 . The method according to  claim 9 , wherein the non-human animal expresses functional GPR146 polypeptide. 
     
     
         11 . The method according to  claim 9 , wherein the non-human animal is wild-type. 
     
     
         12 . The method according to  claim 9 , wherein the non-human animal is a rodent. 
     
     
         13 . A non-human transgenic animal having a functionality-disrupted endogenous GPR146 gene. 
     
     
         14 . The non-human transgenic animal according to  claim 13 ′ wherein the animal has a null mutation. 
     
     
         15 . The non-human transgenic animal according to  claim 13 , wherein the animal is −/− for the GPR146 gene. 
     
     
         16 . A method for identifying an agonist or antagonist of GPR146 gene for the therapy of dyslipidaemia wherein said method comprises the use of a non-human transgenic animal having a functionality-disrupted endogenous GPR146 gene or an isolated cell or tissue thereof. 
     
     
         17 . A method for modeling dyslipidaemia wherein said method comprises the use of a non-human transgenic animal having a functionality-disrupted endogenous GPR146 gene as a model for dyslipidaemia. 
     
     
         18 . A method of determining the presence of susceptibility to dyslipidaemia in an individual, comprising the steps of (i) determining the expression level of GPR146 gene in a sample isolated from the patient, and (ii) determining, compared to a control, whether the individual from which the sample was isolated has or is susceptible to dyslipidaemia. 
     
     
         19 . Use of an exogenous GPR146 polynucleotide, an agent that affects the activity of a GPR146 polypeptide or an agent that increases or decreases the transcription or expression of a GPR146 polynucleotide in the manufacture of a medicament for the prevention or treatment of dyslipidaemia. 
     
     
         20 - 22 . (canceled) 
     
     
         23 . A method for the prevention or treatment of dyslipidaemia wherein said method comprises administering, to a patient in need of such treatment, an exogenous GPR146 polynucleotide, an agent that affects the activity of a GPR146 polypeptide, or an agent that increases or decreases the transcription or expression of a GPR146 polynucleotide. 
     
     
         24 . The method, according to  claim 23 , wherein the dyslipidaemia is Atheromatous disease, Atherosclerosis, Coronary Heart Disease, Dyslipidemia/Dyslipoproteinemia including hypercholesterolemia, Gall Bladder Disease, Impaired glucose tolerance, Insulin resistance, Metabolic Svndrome X, Obesity, Restenosis, Septic shock, Stroke, Type 2 diabetes, Angina pectoris, Transient ischemic attacks (TIAs) or Peripheral artery disease (PAD).